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. 2022 Dec;37(1):2702-2709.
doi: 10.1080/14756366.2022.2126463.

Design and synthesis of some new benzoylthioureido phenyl derivatives targeting carbonic anhydrase enzymes

Mazin A A Najm  1 , Walaa R Mahmoud  2 , Azza T Taher  3   4 , Safinaz E-S Abbas  2 , Fadi M Awadallah  2 , Heba Abdelrasheed Allam  2 , Daniela Vullo  5 , Claudiu T Supuran  5
Affiliations

Design and synthesis of some new benzoylthioureido phenyl derivatives targeting carbonic anhydrase enzymes

Mazin A A Najm et al. J Enzyme Inhib Med Chem. 2022 Dec.

Abstract

The present study aimed to develop potent carbonic anhydrase inhibitors (CAIs). The design of the target compounds was based on modifying the structure of the ureido-based carbonic anhydrase inhibitor SLC-0111. Six series of a substituted benzoylthioureido core were prepared featuring different zinc-binding groups; the conventional sulphamoyl group 4a-d and 12a-c, its bioisosteric carboxylic acid group 5a-d and 13a-c or the ethyl carboxylate group 6a-d and 14a-c as potential prodrugs. All compounds were assessed for their carbonic anhydrase (CA) inhibitory activity against a panel of four physiologically relevant human CA isoforms hCA I and hCA II, and hCA IX, and hCA XII. Compounds 4a, 4b, 4c, 4d, 5d, 12a, and 12c revealed significant inhibitory activity against hCA I that would highlight these compounds as promising drug candidates for the treatment of glaucoma.

Keywords: SLC-0111; Sulphonamides; benzoylthioureido derivatives; carbonic anhydrase.

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Conflict of interest statement

C. T. Supuran is Editor-in-Chief of the Journal of Enzyme Inhibition and Medicinal Chemistry and he was not involved in the assessment, peer review, or decision-making process of this paper. The authors have no relevant affiliations of financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Figures

Figure 1.
Figure 1.
Chemical structure of some ureido and thioureido CAIs.
Figure 2.
Figure 2.
Design of the target compounds as analogues to SCL-0111.
Scheme 1.
Scheme 1.
Reagents and reaction conditions: (i) SOCl2, methylene chloride, reflux, 4–5 h, (ii) NH4SCN, acetone, reflux, 1–3 h, (iii) sulphanilamide or 4-aminobenzoic acid or ethyl 4-aminobenzoate, acetone, reflux, 2–3 h.
Scheme 2.
Scheme 2.
Reagents and reaction conditions: (i) KOH, acetonitrile, R.T, 1–2 h, (ii), SOCl2, methylene chloride, reflux, 4–5 h, (iii) NH4SCN, acetone, reflux, 1–3 h, (iv) sulphanilamide or 4-aminobenzoic acid or ethyl 4-aminobenzoate, acetone, reflux, 2–3 h.
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